Deficiencies in the classical pathway of the complement system are among the strongest genetic risk factors known for developing systemic lupus erythematosus (SLE). Studies from the Carroll lab have shown that murine complement deficiency breaks tolerance to self antigens in Goodnow's HEL/anti-HEL double transgenic model and also in non-autoimmune mice homozygous for fas^lpr. Loss of tolerance is demonstrated by altered B cell fate in the former and ANA positive immune complex glomerulonephritis in the latter. My preliminary observations suggest that in a non-autoimmune genetic background (mixed C57BL/6 and 129), even isolated deficiency of C4 (C4^-/-) or of its receptor CD21/CD35 (Cr2^-/-) are risk factors for developing autoantibodies to DNA. In this proposal I hypothesize that complement deficiency predisposes to human autoimmune disease because components of the classical pathway are required for induction or maintenance of a self-tolerant B cell repertoire. With particular attention to the anti- DNA response that is a hallmark of SLE and SLE nephritis, I will test this hypothesis in several ways. As potential models of human disease, C4^-/- and Cr2^-/- mice will be studied through their natural lifetime with serologic, cytologic and histologic methods to document their spontaneous evolution of anti-DNA autoreactivity and also to seek evidence of renal sequelae. Immunostimulation will be used to potentiate premature autoreactivity in these animals to better delineate defects in B cell regulation, and reconstitution experiments will be designed to confirm the genetic basis of observed autoreactive phenotypes. Lastly, I will generate a novel murine model of SLE by breeding the complement deficient animals to mice transgenic for anti-DNA antibodies. These complement deficient anti-DNA transgenic mice will constitute a unique opportunity to probe complement's role in the tolerogenic mechanisms of B cell receptor editing, clonal deletion and peripheral anergy. By combining immunologic, nephrologic and molecular analyses I propose to elucidate how classical complement deficiency predisposes to SLE.